Tau hyperphosphorylation in the brain of ob/ob mice is due to hypothermia: Importance of thermoregulation in linking diabetes and Alzheimer's disease

• Published in: Neurobiology of disease Vol. 98; pp. 1 - 8
• Main Authors: Gratuze, Maud, El Khoury, Noura B, Turgeon, Andréanne, Julien, Carl, Marcouiller, François, Morin, Françoise, Whittington, Robert A, Marette, André, Calon, Frédéric, Planel, Emmanuel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017; Elsevier
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Body Temperature - drug effects; Body Temperature - physiology; Body Temperature Regulation - drug effects; Body Temperature Regulation - physiology; Caffeine; Caffeine - toxicity; Central Nervous System Stimulants - toxicity; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Hypothermia; Hypothermia - metabolism; Kinase; Leptin; Leptin - administration & dosage; Leptin - metabolism; Life Sciences; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Neurology; ob/ob mice; Phosphatase; Phosphorylation - drug effects; Phosphorylation - physiology; Tau hyperphosphorylation, hippocampus; tau Proteins - metabolism; Temperature; Thermoregulation; PP; H ypothermia; T2DM; L eptin; CamKII; GTT; JNK; ITT; T au hyperphosphorylation, hippocampus; Ca2 + calmodulin-dependent protein kinase II; K inase; Aβ; GSK-3β; PI3K; glycogen synthase kinase-3β; Alzheimer's disease; O b/ O b mice; T emperature; c-Jun N-terminal kinase; Glucose Tolerance Test; Phosphatidylinositol-4,5-bisphosphate 3-kinase; D iabetes mellitus; AD; cdk5; amyloid-β peptide; mitogen activated protein kinase/extracellular signal-regulated kinase; Insulin Tolerance Test; P hosphatase; type 2 diabetes; T hermoregulation; C affeine; phosphatase; cyclin-dependent kinase 5; Alzheimer ' s disease; ERK; Temperature; Diabetes mellitus; Thermoregulation; ob/ob mice; Phosphatase; Tau hyperphosphorylation, hippocampus; Kinase; Leptin; Hypothermia; Caffeine
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2016.10.004

Abstract Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM. Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia. Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.